Submissions for variant NM_001354604.2(MITF):c.958G>C (p.Glu320Gln)

dbSNP: rs1057522775

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000424648	SCV000529405	likely pathogenic	not provided	2016-07-06	criteria provided, single submitter	clinical testing	The E213Q variant in the MITF gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The E213Q variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The E213Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. A missense variant in the same residue, E213D, has been reported as a de novo event in a patient with Waardenburg syndrome type 2A (Leger et al., 2012). In addition, missense variants in nearby residues (N210K, I212S, I212M, R216K, R217G, R217I) have been reported in the Human Gene Mutation Database in association with MITF-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. The E213Q variant is a strong candidate for a pathogenic variant, consistent with the congenital sensorineural hearing loss, ocular albinism, nystagmus, retinal pigmentary changes, hypopigmentation, and patchy hyperpigmented skin macules reported. However the possibility it may be a rare benign variant cannot be excluded.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003766333	SCV004595797	uncertain significance	Tietz syndrome; Waardenburg syndrome type 2A; Melanoma, cutaneous malignant, susceptibility to, 8	2023-10-08	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 213 of the MITF protein (p.Glu213Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of Waardenburg syndrome (Invitae). ClinVar contains an entry for this variant (Variation ID: 387380). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. This variant disrupts the p.Glu213 amino acid residue in MITF. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 32685391). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.